It has been estimated that neurodegenerative diseases presently affect 20 million individuals worldwide. The cost for medical care of patients with Alzheimer's disease (AD), for example, was $91 billion in 2005 and is predicted to increase to $160 billion by 2010 (Burke 2007). Despite considerable research on the etiology and pharmacologic treatment of these diseases, no therapy is known to delay their progression (Schapira and Olanow 2004, Burke 2007). Recently, enhancing the activity of a ubiquitous regulatory protein Akt kinase has beneficial effects upon neurons of the substantia nigra of the midbrain of animals. The increased signaling of Akt mediates the improvement in the health of these neuronal cells in adult normal and aged neurons and confers almost complete protection against neurotoxin induced cell death in rodents (Ries et al, 2006).
AD and other neurodegenerative diseases are called tauopathies because they are characterized by the accumulation of aggregates of the tau protein in neurons. Tau proteins promote the assembly and stabilization of microtubular structures in neurons. The function of tau is regulated by phosphorylation at multiple serine and threonine sites (Sontag et al 1996; Tian and Wang 2002). The state of phosphorylation of tau influences its ability to bind to and enhance the polymerization of microtubules in neurons (Gong et al 2005; Meske et al 2008).
The basis by which increased Akt signaling produces neuroprotection is not certain (Burke 2007). It has been suggested that increased Akt signaling in neurons results in a decrease in the generation of deposits of neurofilaments within neurons leading to their dysfunction and eventual death (Gong et al, 2005. These filaments are composed of a structural protein called Tau. Tau proteins are susceptible to hyper-phosphorylation. Hyper-phosphorylation of tau proteins renders them inactive and results in their aggregation into paired helical filaments. These tangles of tau protein along with plaques of β-amyloid (AB) are the characteristic pathologic features of AD and the other tauopathies (Gong et al 2005).
Control of tau activity by phosphorylation is accomplished by several serine-threonine kinases, particularly glycogen synthase kinase-3β (GSK-3β). GSK-3β itself is regulated by other serine-threonine kinases especially Akt (Grimes and Jope 2001; Liu et al 2005). Activated (phosphorylated) Akt maintains GSK-3β in an inhibited (phosphorylated state). A decrease in Akt activity, that is reduced amounts of phosphorylated Akt, results in activation, that is, decreased phosphorylation of GsK-3β. Activated GSK-3β leads to hyper-phosphorylation of tau, which leads to neuronal cell death (Kaytor and Orr 2002; Baki et al 2008).
There is strong evidence from studies of human Alzheimer's disease and from a mouse model of Alzheimer's disease that failure of adequate levels of phosphorylation of GSK-3β by Akt results in hyper-phosphorylation of tau, generation of tau and amyloid plaques, and neuronal degeneration and death. In early onset familial AD (FAD) there is a defect in presenilins, trans-membrane proteins critical to normal development (Shen et al, 1997; Wong et al 1998). A member of this family, presenilin-1 (PS1), regulates PI3K/Akt signaling (Sherrington et al 1995; Baki et al 2004; Kang et al 2005; Uemura et al 2007). In primary neuronal cultures of cells from PS1−/− mice, Baki et al (2008) showed that there was inadequate PI3K-Akt signaling resulting in decreased phosphorylation of GSK-3β, hyper-phosphorylation of tau, and progressive neurodegeneration. The addition of normal presenilin-1 or of PI3K-Akt increased GSK-3β phosphorylation and suppressed neuronal cell death.
Ries et al. (2006) showed that increasing the concentration of activated Akt inhibits cell death of dopamine neurons of the substantia nigra in mouse model of Parkinson's disease induced by 6-hydroxy dopamine. Increasing Akt activity in the brain of normal adult and also aged mice enhanced the integrity and function of existing dopamine neurons (Ries et al., 2006). In a mouse model of AD, animals with genetically engineered increased amounts of GSK-3β in the forebrain have all the histologic and, to the extent that they can be assessed in the mouse, functional defects of human AD. Elimination of over-expression of GSK-3β by suppression of the transgene results in a return toward normal of all histologic and functional signs of AD (Engel et al 2006).
Neurodegenerative diseases such as AD are frequently characterized by impaired learning and memory. The mechanism(s) responsible for these most troublesome symptoms are associated with death of neuronal cells. At a molecular level, the basis for changes in memory formation and consolidation has been linked to the activity of histone deacetylases chromatin structures (Korzus et al, 2004; Levenson et al, 2004). Beglopoulos and Shen (2006) found that inhibitors of phosphodiesterase 4 and histone deacetylases reduce memory deficits and neurodegeneration in animal models of AD affecting cAMP response element (CRE) genes. Recently, Fischer et al (2007) reported improved learning behavior and access to long-term memories after significant neuronal loss and brain atrophy can be reestablished in a mouse model by environmental enrichment and by treatment with inhibitors of histone deacetylases (see reviews and commentaries by Sweat, 2007; Mangan and Levenson 2007; Albert 2007; Abel and Zukin; 2008).
Acetylation and deacetylation have a critical role in regulation of gene expression, cellular proliferation, development and differentiation, with aberrant deacetylation leading to a multitude of disorders (Abel and Zukin, 2008). Histone deacetylase inhibitors (HDACi) have anti-inflammatory and neuroprotective effects in models of stroke and Alzheimer's disease (AD) (Abel and Zukin, 2008). Inhibitors of protein phosphatase 2A (PP2Ai), primarily the shellfish toxin, okadaic acid, have neuroprotective effects in some model systems but are injurious in others (Tian and Wang, 2002).
Thus, there is substantial evidence that AD is a pathologic condition resulting from inadequate activity of the enzyme Akt and excessive activity of GSK-3β and that reduction of GSK-3β activity may reduce the severity of precipitated tau proteins, with a lessening of neurological deficit. In addition, there appears to be a poorly understood component of neurodegenerative diseases related to excessive histone deacetylase activity, or at least a condition of reduced acetylation of certain histones that is corrected by increased acetylation resulting in improved learning and memory. Non-toxic drugs that protect and foster the survival of acute and chronically diseased neurons are urgently needed.
The compounds described herein reduce the activity of GSK-3β and increase the acetylation of neuronal histones.